Age (>60yrs) is associated with increased mortality after acute kidney injury (AKI) with survivors being left with chronic kidney disease and on dialysis costing $10 billion per year. Components of the underlying mechanism that lead from AKI to failure to recover kidney function and CKD have been identified using animal models including ischemia-reperfusion injury. Increased apoptosis, inflammation and deposition of extracellular matrix result in renal fibrosis and renal failure. Persistent activation of pro-inflammatory and pro-fibrotic signals are important mediators of this process. It is not understood well why older individuals are at increased risk for delayed, incomplete or absent recovery after AKI. The NF-kappaB pathway has been identified as an activator of age-related transcriptional changes in human and rodents and is thought to mediate development of both GS and TIF following tissue injury. Micro-RNAs have recently been found to play an important role in coordinating the apoptotic and pro-fibrotic response to NF-kappaB activation. microRNAs (miRs), are small RNA molecules (19-22 nucleotides long) that coordinate pathways of gene expression via partial complementary to target mRNAs. They are a particularly attractive avenue for investigation because of their therapeutic potential as long-lasting drugs that can modulate molecular pathways. Our preliminary data show delayed recovery from ischemia-reperfusion injury in young adult miR-21 knockout mice. In addition, miR-21 inhibits apoptosis in cultured renal epithelial cells. Because we detected increasing miR-21 expression in the kidney during aging, we hypothesize that this increased miR-21 expression plays a protective role that prevents activation of the apoptotic and pro-fibrotic pathway activation in response to injury through inhibiting components of the NF-kappaB pathway and crosstalk with p53 and TGF-beta signaling. We propose to determine whether loss of miR-21 alters the response to ischemia-reperfusion injury associated with aging by examining renal function, histologic changes and cellular mechanisms known to mediate IR injury in miR-21 null mice. Furthermore, we will define the underlying mechanism of age-associated changes and its regulation by miR-21 in the renal response to IR injury using genome-wide expression profiling and a systems biology approach to compare patterns of transcriptional network structures. We expect that old mice lacking miR-21 will exhibit increased susceptibility to ischemia-reperfusion than young mice and their wildtype litter-mates with an intact miR-21 regulatory machinery. Demonstration of this protective relationship for miR-21 will open up the possibility that this micro-RNA could be used therapeutically.